Sarcopenia is an important factor in reducing Activity of Daily Life. Sarcopenia has also been linked to insulin resistance. It has been reported that autophagy is one of the mechanisms as a cause of sarcopenia. We focused on autophagy as a system that can regulate both sarcopenia and metabolic syndrome in skeletal muscle and revealed that non-receptor tyrosine kinase Fyn not only participates in metabolic syndrome but also regulates autophagy regulating sarcopenia through STAT3 regulation (Cell metabolism 2010, Cell Rep. 2012). We proceeded with further studies and demonstrating that Fyn-dependent STAT3 phosphorylation by IL6, which is involved in chronic inflammation and metabolic syndrome, was observed in mouse C2C12 myotube cells. Autophagy was decreased in those cells by both IL6-dependent and Fyn-dependent mechanisms. The binding of STAT3 and Fyn was confirmed by immunoprecipitation in an in vitro system. Furthermore, in the denervated mouse model, not only both Fyn and IL6 gene expressions were increased but the expression and phosphorylation levels of STAT3 were also augmented, while the autophagy activity was decreased. We believe that a denervated mouse model alone is not sufficient as a model for sarcopenia, thus we next introduced a hind limb suspension mouse model that promotes disuse atrophy by suspending the hind limb. Using this model, we found that muscle atrophy was observed mainly in the soleus muscle, tibialis anterior muscle, and the gastrocnemius muscle. In addition, the findings are consistent with autophagy failure, and accumulation of glycogen (PAS staining) was observe. Increase of both IL6 and STAT3 expression/phosphorylation were observed in the muscles of those mice. Autophagy activity, examined by intraperitoneal administration of colchicine, was decreased. These results strongly suggest that Fyn is involved not only in the metabolic syndrome but also in the pathogenesis of sarcopenia, and may lead to a better understanding of the pathology of sarcopenia obesity and the development of therapeutic methods.


E. Yamada: None. R. Uehara: None. Y. Nakajima: None. K. Horiguchi: None. E. Ishida: None. S. Matsumoto: None. S. Okada: None. C.C. Bastie: None. M. Yamada: None.

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